Salmonella enterica serovar Typhi (S. typhi) and paratyphi (S. paratyphi), the causes of typhoid fever, results in more than 200,000 annual deaths (Parry et al., N. Engl. J. Med. 347:1770-1782; Crump et al., 2008, Antimicrob. Agents Chemother. 52:1278-1284; Raffatellu et al., 2008, J. Infect. Dev. Ctries. 2:260-266; Butler, 2011, Clin. Microbiol. Infect. 17:959-963; Crump and Mintz, 2010, Clin. Infect. Dis. 50:241-246). Unlike other Salmonella serovars, which typically cause self-limiting gastroenteritis, S. typhi and S. paratyphi cause a systemic, life-threatening disease (Parry et al., N. Engl. J. Med. 347:1770-1782). The genomes of S. typhi and S. paratyphi contain a dearth of unique virulence factors that are not found in non-typhoidal serovars, and the molecular bases for its unique virulence properties and clinical presentation are unknown (Sabbagh et al., 2010, FEMS Microbiol. Lett. 305:1-13; Parkhill et al., 2001, Nature 413:848-852).
One of the few S. typhi- and S. paratyphi-specific factors that has been shown to directly impact its interaction with host cells is an AB-type toxin dubbed typhoid toxin (Haghjoo and Galan, 2004, Proc. Natl. Acad. Sci. USA 101:4614-4619; Spano et al., 2008, Cell Host Microbe 3:30-38; Spano and Galan, 2008, Curr. Opin. Microbiol. 11:15-20). AB family toxins consists of enzymatically active A subunits that interfere with host functions, and B subunits that deliver the toxins to their target cells through receptor-mediated endocytosis (Beddoe et al., 2010, Trends Biochem. Sci. 35:411-418; Merritt and Hol, 1995, Curr. Opin. Struct. Biol. 5:165-171). Unlike typical AB toxins, typhoid toxin is composed of two A subunits, PltA and CdtB, which are homologs of the A subunits of the pertussis and cytolethal distending toxins, respectively (Spano et al., 2008, Cell Host Microbe 3:30-38). Its single B subunit, PltB, is a homolog of one of the components of the heteropentameric B subunit of pertussis toxin. Although the cellular targets of the ADP-ribosyl transferase activity of PltA have not yet been identified, CdtB is a deoxyribonuclease that is targeted to the nucleus where it inflicts DNA-damage and induces cell cycle arrest (Haghjoo and Galan, 2004, Proc. Natl. Acad. Sci. USA 101:4614-4619; Lara-Tejero and Galan, 2000, Science 290:354-357; Lara-Tejero and Galan, 2002, Trends in Microbiology 10:147-152).
This toxin is remarkable in that the activities of two powerful toxins seem to have been co-opted into a single toxin with unique biology. There are currently no effective vaccines to protect against typhoid fever, and in particular to protect young children, the most susceptible population, against typhoid fever. Moreover, there are currently no effective and specific diagnostic tools for typhoid fever, and multiple antibiotic resistant S. Typhi is rapidly emerging, with the prospects of typhoid fever being untreatable by antibiotics becoming a real threat (Butler, 2011, Clin. Microbiol. Infect. 17:959-963).
There are currently no WHO prequalified vaccines considered suitable for widespread use to protect against typhoid fever, and in particular to protect young children, the most susceptible population. Furthermore, the major strategy of recent vaccine efforts has been directed towards the Vi antigen surface polysaccharide, which is exclusively encoded by S. Typhi. Consequently, there are no vaccines currently available to protect against S. Paratyphi A, which does not encode Vi antigen and is estimated to be responsible for as much as ˜20-50% of all enteric fever cases.
Thus, there is a need in the art for compositions and methods for preventing, treating and diagnosing typhoid fever. The present invention addresses this unmet need.